EP1802298A2 - Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente - Google Patents

Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente

Info

Publication number
EP1802298A2
EP1802298A2 EP05794149A EP05794149A EP1802298A2 EP 1802298 A2 EP1802298 A2 EP 1802298A2 EP 05794149 A EP05794149 A EP 05794149A EP 05794149 A EP05794149 A EP 05794149A EP 1802298 A2 EP1802298 A2 EP 1802298A2
Authority
EP
European Patent Office
Prior art keywords
formula
group
coumarin
obliquin
coumarin ether
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05794149A
Other languages
German (de)
English (en)
Other versions
EP1802298B1 (fr
Inventor
Antoine De Saizieu
Ann Fowler
Regina Goralczyk
Bernd Mussler
Goede Schueler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Priority to EP05794149A priority Critical patent/EP1802298B1/fr
Publication of EP1802298A2 publication Critical patent/EP1802298A2/fr
Application granted granted Critical
Publication of EP1802298B1 publication Critical patent/EP1802298B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/385—Concentrates of non-alcoholic beverages
    • A23L2/39—Dry compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L7/00—Cereal-derived products; Malt products; Preparation or treatment thereof
    • A23L7/10—Cereal-derived products
    • A23L7/117—Flakes or other shapes of ready-to-eat type; Semi-finished or partly-finished products therefor
    • A23L7/126—Snacks or the like obtained by binding, shaping or compacting together cereal grains or cereal pieces, e.g. cereal bars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Novel agents for preventing and treating disorders connected to impaired neurotransmis ⁇ sion Novel agents for preventing and treating disorders connected to impaired neurotransmis ⁇ sion
  • the present invention refers to coumarin. ethers for use as medicaments, especially for the treatment of disorders connected to impaired neurotransmission, as well as to dietary and pharmaceutical compositions and plant materials and extracts containing such coumarin ethers and their uses.
  • Neurotransmitters, drugs and brain function R.A. Webster (ed), John Wiley & Sons, New York, 2001, p. 187-211, 289-452, 477-498).
  • Increase in neurotrans ⁇ mission is achieved by increasing the concentration of the neurotransmitter in the synaptic cleft thus making it available for increased or prolonged neurotransmission through inhibi- tion of re-uptake into the pre-synaptic nerve end, or by preventing neurotransmitter catabo- lism by inhibition of degrading enzymes such as monoaminooxidase A and B.
  • Tricyclic antidepressant compounds such as imipramine, amitriptyline, and clomipramine e.g. inhibit the re-uptake of serotonin and noradrenaline. They are widely regarded as among the most effective antidepressants available, but they have a number of disadvantages because they interact with a number of brain receptors, e.g. with cholinergic receptors. Most importantly, TCAs are not safe when taken in overdose, frequently show ⁇ ing acute cardiotoxicity.
  • SSRIs selective serotonin re ⁇ uptake inhibitors
  • fluoxetine serotonin re ⁇ uptake inhibitors
  • paroxetine sertraline
  • citalopram fluvoxamine
  • Best&tfgungskop ⁇ block the serotonin transporter (SERT), a high affinity sodium chloride-dependent neuro ⁇ transmitter transporter that terminates serotonergic neurotransmission by uptake of sero ⁇ tonin. They have been proven as effective in the treatment of depression and anxiety, and are usually better tolerated than TCAs. These medications are typically started at low dos- ages and may be increased until they reach a therapeutic level. A common side effect is nausea. Other possible side effects include decreased appetite, dry mouth, sweating, infec ⁇ tion, constipation, yawn, tremor, sleepiness and sexual dysfunction.
  • MAOs monoaminooxidases
  • modulators of neurotransmission exert pleiotropic effects on mental and cog- nitive functions.
  • R 1 is H, OH or (E)-3-methyl-but-2-enyl
  • R 2 is selected from the group consisting of methyl, 3-(4,5-dihydro-5,5-dimethyl-4-furanon-2-yl)-2-(E/Z)-butenyl, (E/Z)-3,7- dimethylocta-2,6-dienyl, 7-hydroxy-3,7-dimethyl-2-octen-6-on-yl and (E/Z,E/Z)-11- acetyloxy-SJJlJl-tetramethyl-undeca ⁇ J-dien-lO-on-yl
  • the invention relates to the use of a coumarin ether of the formula I as defined above for the manufacture of a composition for the treatment of a disorder con ⁇ nected to impaired neurotransmission, particularly for the manufacture of an antidepres ⁇ sant, a mood improver, a stress reliever, a condition improver, a reducer of anxiety and/or a reducer of obsessive-compulsive behaviour.
  • the invention relates to a dietary composition containing at least one coumarin ether of the formula I as defined above as well as to a pharmaceutical composi ⁇ tion containing at least one coumarin ether of the formula I as defined above and a conven ⁇ tional pharmaceutical carrier.
  • the invention relates to a method for the treatment of a disorder connected to im ⁇ paired neurotransmission in animals including humans, said method comprising adminis ⁇ tering an effective dose of a coumarin ether of the formula I as defined above to animals including humans which are in need thereof.
  • Animals in the context of the present invention include humans and encompass mammals, fish and birds.
  • Preferred "animals" are humans, pet animals and farm animals. Examples for pet animals are dogs, cats, birds, toy fish, guinea pigs, (jack) rabbits, hares and ferrets. Examples for farm animals are fish, pigs, horses, ruminants (cattle, sheep and goat) and poultry.
  • the coumarin ether of the formula I is selected from the group consisting of obliquin (compound of the formula It; see Fig. 1), xanthyletin (compound of the formula HI; see Fig. 1), suberosin (compound of the formula IV; see Fig. 1), 7-geranyloxycoumarm (compound of the formula V; see Fig. 1), ⁇ '-dehydromarmin (compound of the formula VI; see Fig. 1), geiparvarin (compound of the formula VHI; see Fig. 1), O-acetylcolumbianetin (compound of the formula IX; see Fig. 1) and the com ⁇ pound of the formula VQ (see Fig. 1). More preferably the coumarin ether of the formula I is obliquin, most preferably the coumarin ether of the formula I is (5)-obliquin.
  • coumarin ether of the formula I also encompasses any material or extract of a plant containing such a coumarin ether of the formula I, especially any material or extract of a plant containing at least 90 weight-% of such a coumarin ether of the formula I based on the total weight of the plant material or extract.
  • material of a plant and “plant material” used in the context of the present invention mean any part of a plant.
  • Obliquin means the racemic mixture as well as pure R-obliquin or pure S-obliquin or any mixture of them. Obliquin can be isolated from plants like, but not limited to, Cedrelopsis grevei, Ptaeroxylon obliquum, Leontopodium alpinum, Helichrysum ssp., Ifloga spicata, Nidorella anomala, Cneorum tricoccum, Phaenocoma prolifera and Cedrelopsis microfo- liata (Journal of Natural Products 2002, 65, 1349-1352).
  • any material or extract of these plants or any other plant material or extract con ⁇ taining obliquin is also encompassed by this expression.
  • "Obliquin” means both "natural” (isolated) and “synthetic” (manufactured) obliquin.
  • 7-Geranyloxycoumarin also called “aurapten” can be isolated from plants like the follow ⁇ ing, but not limited to Citrus ssp., Aegle martnelos, Poncirus trifoliata, Afraegle panicu- lata, Severinia buxifolia, Atalantia monophylla, Ptelea trifoliata and Fortunella hindsii. Therefore, any material or extract of these plants or any other plant material or extract con ⁇ taining 7-geranyloxycoumarin is also encompassed by this expression.
  • “7-Geranyloxy- coumarin” means both "natural” (isolated) and “synthetic” (manufactured) 7-geranyloxy ⁇ coumarin.
  • Suberosin can be isolated from plants like the following, but not limited to Plumbago zey- lanica, Seseli ssp., Heracleum candicans, Citrus ssp., Prangos lipskyi and Prangos lo- phoptera. Therefore, any material or extract of these plants or any other plant material or extract containing suberosin is also encompassed by this expression.
  • “Suberosin” means both "natural” (isolated) and “synthetic” (manufactured) suberosin.
  • the compound of formula VII (CAS [374702-57-5]) can be isolated from Ferula tadshi- korum and other plants. Therefore, any material or extract of these plants or any other plant material or extract containing the compound of formula VII is also encompassed by this expression.
  • “Compound of formula VH” means both "natural” (isolated) and “synthetic” (manufactured).
  • 6 * -Dehydromarrnin can be isolated from the fruit of Geijera parviflora and other plants. Therefore, any material or extract of these plants or any other plant material or extract con ⁇ taining 6'-dehydromarmin is also encompassed by this expression.
  • 6'-Dehydromarmin means both "natural” (isolated) and “synthetic” (manufactured) 6'-dehydromarmin.
  • Geiparvarin can be isolated from the leaves of Geijera parviflora and other plants. There- fore, any material or extract of these plants or any other plant material or extract containing geiparvarin is also encompassed by this expression.
  • Geiparvarin means both "natural” (isolated) and “synthetic” (manufactured) geiparvarin.
  • Geiparvarin can be prepared according to the process described in Journal of Organic Chemistry 1985, 50(21), 3997-4005 or in Bioorganic & Medicinal Chemistry Letters 2002, 12(24), 3551-3555.
  • O-Acetylcolu ⁇ ibianetin can be isolated from plants like, but not limited to Cnidium monnieri and Angelica ssp. Therefore, any material or extract of these plants is also en ⁇ compassed by this expression.
  • O-Acetylcolumbianetin means both "natural” (isolated) and “synthetic” (manufactured) O-acetylcolumbianetin.
  • the dietary compositions according to the present invention may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsi- fiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (sol ⁇ vents), flowing agents, taste masking agents, weighting agents, jellyfying agents, gel form ⁇ ing agents, antioxidants and antimicrobials.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsi- fiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents
  • dietary compositions comprises any type of nutrition such as (fortified) food/feed and beverages including also clinical nutrition, and also dietary supplements.
  • the pharmaceu ⁇ tical compositions according to the present invention may further contain conventional pharmaceutical additives and adjuvants, excipients or diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • the carrier material can be organic or inorganic inert carrier material suitable for oral/paren- teral/injectat ⁇ e administration.
  • the dietary and pharmaceutical compositions according to the present invention may be in any galenic form that is suitable for administrating to the animal body including the human body, especially in any form that is conventional for oral administration, e.g. in solid form such as (additives/supplements for) food or feed, food or feed premix, fortified food or feed, tablets, pills, granules, dragees, capsules, and effervescent formulations such as pow ⁇ ders and tablets, or in liquid form such as solutions, emulsions or suspensions as e.g. bev ⁇ erages, pastes and oily suspensions.
  • the pastes may be filled into hard or soft shell cap- sules, whereby the capsules feature e.g.
  • a matrix of (fish, swine, poultry, cow) gelatin, plant proteins or ligninsulfonate examples are forms for trans ⁇ dermal, parenteral or injectable administration.
  • the dietary and pharmaceutical composi ⁇ tions may be in the form of controlled (delayed) release formulations.
  • Examples of food are dairy products such as yoghurts.
  • Examples of fortified food are cereal bars, bakery items such as cakes and cookies.
  • Beverages encompass non-alcoholic and alcoholic drinks as well as liquid preparations to be added to drinking water and liquid food.
  • Non-alcoholic drinks are e.g. soft drinks, sport drinks, fruit juices, lemonades, teas and milk based drinks.
  • Liquid food are e.g. soups and dairy products (e.g. muesli drinks).
  • the coumarin ethers of formula I with the definitions of R 1 , R 2 and R 3 and the preferences as given above can be used for the manufacture of medicaments for the treatment of a dis ⁇ order connected to impaired neurotransmission.
  • treatment also encompasses co-treatment as well as prevention.
  • prevention can be the prevention of the first occurrence (primary prevention) or the prevention of a reoccurence (secondary prevention).
  • the present invention is also directed to a method for the prevention of a disorder connected to impaired neurotransmission in animals including humans, said method com ⁇ prising administering an effective dose of a coumarin ether of the formula I with the defini ⁇ tions of R 1 , R 2 and R 3 and the preferences as given above to animals including humans which are in need thereof.
  • an effective dose of a coumarin ether of the for- mula I with the definitions of R 1 , R 2 and R 3 and the preferences as given above may espe ⁇ cially be used for maintaining the mental well-being, for maintaining a balanced cognitive function, for helping to reduce the risk of mood swings, for helping to retain a positive mood and for supporting cognitive wellness.
  • disorders also encompasses diseases.
  • Antidepressants are medicaments for treating mental, behavioural and emotional/affective, neurotic, neurodegenerative, eating and stress related disorders such as e.g. unipolar de- pression, bipolar depression, acute depression, chronic depression, subchronic depression, dysthymia, postpartum depression, premenstrual dysphoria/syndrom (PMS), climacteric depressive symptoms, aggression, attention deficit disorders (ADS), social anxiety disor ⁇ ders, seasonal affective disorders, anxiety (disorders), fibromyalgia syndrome, chronic fa ⁇ tigue, sleep disorders (insomnia), post-traumatic stress disorders, panic disorders, obses- sive compulsive disorders, restless leg syndrome, nervousness, migraine/primary head ⁇ aches and pain in general, emesis, bulimia, anorexia nervosa, binge eating disorder, gastro ⁇ intestinal disorders, burn out syndrome, irritability and tiredness.
  • unipolar de- pression bipolar depression, acute depression
  • Antidepressants can also be used for (the manufacture of compositions for) primary and secondary prevention and/or the treatment of neurocognitive impairment. Furthermore they are also effective in the treatment of depressive symptoms or other symptoms related to disturbed neurotransmission occurring as comorbidity in chronic diseases such as cardio- vascular diseases, strokes, cancer, Alzheimer disease, Parkinson disease, and others.
  • the coumarin ethers of the formula I with the definitions of R 1 , R 2 and R 3 and the prefer ⁇ ences as given above as well as plant materials and plant extracts (essentially) containing them and dietary/pharmaceutical compositions containing them are thus suitable for the treatment of animals including humans.
  • Especially pet animals and farm animals can be in conditions in need of enhanced or im ⁇ proved neurotransmission.
  • Such conditions e.g. occur after capture or transport or with housing, when the animals develop analogous disorders and are distressed or aggressive, or display stereotypic behaviour, or anxiety and obsessive-compulsive behaviour.
  • the coumarin ethers of the formula I with the definitions of R , R and R and the preferences as given above can be used in general as antidepressants for animals including humans, preferably for humans, pet animals and farm animals.
  • the coumarin ethers of the formula I with the definitions of R 1 , R 2 and R 3 and the preferences as given above find use as mood im ⁇ prover in general as well as for the manufacture of compositions for such use (plant mate ⁇ rials/extracts; dietary/pharmaceutical compositions).
  • “Mood improver” or “emotional well- ness booster” means that the mood of a person treated with it is enhanced, that the self es ⁇ teem is increased and/or that negative thoughts and/or negative tension are/is reduced. It also means the emotions are balanced and/or that the general, especially the mental, well being is improved or maintained, as well as that the risk of mood swings is (helped to be) reduced and that the positive mood is (helped to be) retained.
  • compositions comprising an effective dose of them are useful for the treatment, prevention and the alleviation of stress related symptoms, for the treatment, prevention and alleviation of symptoms related to working overload, exhaus- tion and/or burn out, for the increase of the resistance or tolerance to stress and/or to favor and facilitate the relaxation in normal healthy individuals i.e. such compositions have an effect as "stress reliever".
  • coumarin ethers of the formula I with the definitions of R , R and R and the preferences as given above as well as compositions comprising an effective dose of them are useful for the treatment, prevention and alleviation of anxiety and obsessive- compulsive behaviour in humans and animals.
  • a further embodiment of the present invention relates to the use of coumarin ethers of the formula I with the definitions of R 1 , R 2 and R 3 and the preferences as given above and to the use of compositions containing them (plant extracts; dietary/pharmaceutical composi ⁇ tions) as "condition improver", i.e. as means to reduce irritability and tiredness, to reduce or prevent or alleviate physical and mental fatigue, to favour undisturbed sleep, that is to act against insomnia and sleep disorders and to improve sleep, and to increase energy in more general terms, especially to increase the brain energy production, in diseased or nor ⁇ mal healthy individuals.
  • condition improver i.e. as means to reduce irritability and tiredness, to reduce or prevent or alleviate physical and mental fatigue, to favour undisturbed sleep, that is to act against insomnia and sleep disorders and to improve sleep, and to increase energy in more general terms, especially to increase the brain energy production, in diseased or nor ⁇ mal healthy individuals.
  • cognition improvement in general, and especially for maintenance or improvement of attention and concentration of the memory and of the capacity for remembering, of the learning ability, of the language processing, of problem solving and of intellectual functioning; for improvement of the short-term memory; for in ⁇ creasing the mental alertness; for enhancing the mental vigilance; for reducing the mental fatigue; for supporting cognitive wellness, for maintaining balanced cognitive function, for the regulation of hunger and satiety as well as for the regulation of motor activity.
  • the present invention not only refers to coumarin ethers of the formula I with the defini ⁇ tions of R 1 , R 2 and R 3 and the preferences as given above and their compositions (i.e. plant extracts essentially containing them; dietary/pharmaceutical compositions containing them) for use as medicaments, especially for the treatment of disorders connected to im ⁇ paired neurotransmission, but also for the methods for the treatment of such disorders themselves, as already mentioned above.
  • pet animals or farm animals whose disorders are associated with housing, capture or transport are treated and which may ap ⁇ pear in form of anxiety or obsessive-compulsive behaviour.
  • a suitable daily dosage of a coumarin ether of the formula I may be within the range from 0.001 mg per kg body weight to about 20 mg per leg body weight per day. More preferred is a daily dosage of about 0.01 to about 10 mg per kg body weight, and especially preferred is a daily dosage of about 0.05 to 5.0 mg per kg body weight.
  • the amount of a plant material or plant extract containing such coumarin ether of the formula I can be calculated accordingly.
  • the coumarin ether of the formula I is suitably present in an amount from about 0.1 mg to about 1000 mg, preferably from about 1 mg to about 500 mg per dosage unit.
  • the coumarin ether of the formula I is suitably present in an amount of from about 0.0001 (1 mg/kg) to about 5 weight-% (50 g/kg), preferably from about 0.001 % (10 mg/kg)to about 1 weight-%, (10 g/kg) more pref ⁇ erably from about 0.01 (100 mg/kg) to about 0.5 weight-% (5 g/kg), based upon the total weight of the food or beverage.
  • the amount of the coumarin ether of the formula I with the definitions of R 1 , R 2 and R 3 and the preferences as given above is 10 to 30 mg per serving, i.e. 120 mg per kg food or drink.
  • a suitable daily dosage of a coumarin ether of the formula I may be within the range from 0.001 mg per kg body weight to about 1000 mg per kg body weight per day. More preferred is a daily dosage of about 0.1 mg to about 500 mg per kg body weight, and especially preferred is a daily dosage of about 1 mg to 100 mg per kg body weight.
  • Example 1 a racemic mixture of obliquin obtained from MicroSource Discovery Sys ⁇ tems Inc, 21 George Washington Plaza, Gaylordsville, CT 06755 USA was used. It had a purity of > 96%.
  • examples 2 and 3 a racemic mixture of obliquin synthesized according to J. Chem. Soc. (C) 1969, 526-531 was used. Xanthyletin were obtained from Micro- source as well. 7-geranyloxycoumarin, 6'-dehydromarmin, geiparvarin, (iS)-O-acetylcolum- bianetin and suberosin were obtained from APIN Chemicals, 43d Milton Park, Abingdon, Oxon, OX14 4RU, United Kingdom. And the compound of the formula VII was obtained from InterBioScreen Ltd., Bistitutsky Prospect, 7a 142432 Chernogolovka, Russia.
  • Example 1 Serotonin uptake inhibition and labeled citalopram displacement by coumarin ethers of the formula I.
  • HEK-293 cells stably expressing the human serotonin re-uptake transporter (hSERT) were obtained from R. Blakely, Vanderbilt University, USA. The cells were routinely grown in Dulbeco's Modified Eagles Medium, purchased from Bioconcept, Allschwil, Switzerland containing 10% fetal calf serum, penicillin, streptomycin, L-glutamine and the antibiotic G418 and passaged by trypsinisation.l day prior to the assay cells were seeded in the above mentioned medium.
  • Membranes containing hSERT were prepared from the above cell line according to Galli et al, Journal of Experimental Biology 1995, 198, 2197-2212. 3 ⁇ g of membrane protein and 0.8 mg of wheat germ aglutinin coated SPA® (scintillation proximity assay) beads (Amer ⁇ sham Biosciences GE Healthcare, Slough, UK) per data point were mixed with radio ⁇ labeled (3H) citalopram (Amersham Biosciences GE Healthcare, Slough, UK) until a final concentration of 3.3 nM in 5OmM Tris-HCl, 300 mM NaCl (pH 7.4). After incubation for 18 hours at room temperature, the bound citalopram was quantified by liquid scintillation counting.
  • the effect of the coumarin ethers of formula I on the serotonin uptake and the citalopram binding was determined by its inclusion in the assay at a range of concentrations between 0.03 and 100 ⁇ M for 10 minutes prior to and during the addition of (3H) serotonin / citalo ⁇ pram. Serotonin uptake via the transporter and citalopram binding were both inhibited by the coumarin ethers of formula I in a dose dependent manner.
  • the calculated inhibition constants Kj derived from the measured IC50 using the Cheng - Prusoff equation (Y.C. Cheng, W.H. Prusoff, Biochem. Pharmacol. 1973, 22, p. 3099 - 3108), for inhibition of serotonin uptake and citalopram binding by coumarin ethers of the formula I are shown in Table 1.
  • Table 1 Inhibition constants for inhibition of serotonin uptake into transfected HEK-293 cells and displacement of labeled citalopram from hSERT containing membranes by cou ⁇ marin ethers of formula I.
  • Example 2 Monoaminooxidase inhibition by obliquin.
  • MAO-A enzyme As substrates for MAO-A enzyme (Sigma Nr. M7316) p-tyramine and as substrate for MAO-B enzyme (Sigma Nr. M7441) benzylamine were used.
  • concentration of MAO- A enzyme was 8 Units/ml, and that of MAO-B 4 Units/ml in the working solution.
  • Table 2 Inhibition of MAO-A with increasing concentrations of obliquin.
  • the "Behavioural Despair Test” or “Porsolt's Forced Swim Test” is a validated animal model for depression (see T. Nagatsu, NeuroToxicology 2004, 25, 11-20, especially p. 16, right column in the middle, in combination with Porsolt et al., Arch. Int. Pharmacodyn. 1977, 229, 327-336). It responds to enhancement of the transmission of several neuro ⁇ transmitters including serotonine, dopamine and noradrenaline.
  • mice were studied per each of the four groups.
  • the test was performed blind, i.e. the person carrying out the experiment was different from the person injecting the mice and didn't thus know to which of the four groups each mouse belonged.
  • Obliquin was evaluated at 3 doses each: at 10, 30, and 80mg/kg body weight, administered intraperitonally 30 minutes before the test, and compared with a control group.
  • the thus administered obliquin was dissolved in a saline solution containing 3 weight-% DMSO and 3 weight-% Tween® 80 (so called "vehicle").
  • vehicle consist- ing of the saline solution containing 3 weight-% DMSO and 3 weight-% Tween® 80 was administered intraperitonally.
  • Example 4 Marble Burying Test as test for anxiety like or obsessive compulsive behaviour
  • SSRIs e.g. fluvoxamine, fluoxetine, citalopram
  • tricyclic antidepressants e.g. imipramine, desipramine
  • selective noradrenaline uptake inhibitors e.g. reboxetine
  • the model may reflect either anxiety-like-or obsessive-compulsive- behaviour (see De Boer and Koolhaas, Euro- pean Journal of Pharmacology 2003, 463, page 145-161).
  • 7-GeranyI-oxycoumarin was evaluated at 3, 10 and 30 mg/kg, administered i.p. 30 min- utes before the test, and compared with a vehicle control group. 7-Geranyl-oxycoumarin was dissolved in a saline solution containing 3 weight-% DMSO and 3 weight-% Tween®
  • vehicle 80 (so called "vehicle”).
  • vehicle consisting of the saline solution containing 3 weight-% DMSO and 3 weight-% Tween® 80 was administered intraperito- nally.
  • Fluoxetine 32 mg/kg, administered under the same experimental conditions, was used as a reference substance.
  • a soft gelatin capsule (500 mg) may be prepared comprising the following ingredients:
  • Two capsules per day for 3 months may be administered to a human adult for the treatment of mild chronic dysthymia.
  • a soft gelatin capsule (600 mg) may be prepared comprising the following ingredients:
  • Example 7 Preparation of a tablet
  • a 400 mg-tablet may be prepared comprising the following ingredients:
  • one tablet may be taken twice daily for 3 months.
  • the ready-to-drink soft drink contains ca. 30 mg Obliquin per serving (250 ml).
  • Example 9 Preparation of a fortified non baked cereal bar
  • Obliquin is premixed with skim milk powder and placed in a planetary bowl mixer. Corn ⁇ flakes and rice crispies are added and the total is mixed gently. Then the dried and cut ap ⁇ ples are added.
  • a first cooking pot sugar water and salt are mixed in the amounts given above (solution 1).
  • glucose invert and sorbitol syrup are mixed in the amounts given above (solution 2).
  • a mixture of baking fat, palmkernel fat, lecithin and emulsifier is the fat phase.
  • Solution 1 is heated to 110°C.
  • Solution 2 is heated to 113°C and then cooled in a cold water bath. Afterwards solution 1 and 2 are combined. The fat phase is melted at 75°C in a water bath.
  • the fat phase is added to the combined mixture of solu- tion 1 and 2.
  • Apple flavour and citric acid are added to the liquid sugar-fat mix.
  • the liquid mass is added to the dry ingredients and mixed well in the planetary bowl mixer.
  • the mass is put on a marble plate and rolled to the desired thickness.
  • the mass is cooled down to room temperature and cut into pieces.
  • the non baked cereal bar contains ca. 25 mg obliquin per serving (30 g). For general well-being and energizing 1-2 cereal bars may be eaten per day.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nutrition Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Feed For Specific Animals (AREA)
  • Fodder In General (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
EP05794149A 2004-10-22 2005-10-21 Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente Expired - Lifetime EP1802298B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05794149A EP1802298B1 (fr) 2004-10-22 2005-10-21 Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP04025165 2004-10-22
PCT/CH2005/000621 WO2006042441A2 (fr) 2004-10-22 2005-10-21 Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente
EP05794149A EP1802298B1 (fr) 2004-10-22 2005-10-21 Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente

Publications (2)

Publication Number Publication Date
EP1802298A2 true EP1802298A2 (fr) 2007-07-04
EP1802298B1 EP1802298B1 (fr) 2008-12-31

Family

ID=36154615

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05794149A Expired - Lifetime EP1802298B1 (fr) 2004-10-22 2005-10-21 Nouveaux agents de prevention et de traitement de troubles associes a une neurotransmission deficiente

Country Status (9)

Country Link
US (1) US8044094B2 (fr)
EP (1) EP1802298B1 (fr)
JP (2) JP2008517879A (fr)
KR (1) KR20070068400A (fr)
CN (2) CN101703239A (fr)
AT (1) ATE418980T1 (fr)
DE (1) DE602005012132D1 (fr)
ES (1) ES2320686T3 (fr)
WO (1) WO2006042441A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802723B2 (en) * 2005-01-21 2014-08-12 Arkray, Inc. Metabolic syndrome-improving agent and medicine, supplement, functional food and food additive containing the same
US8329239B2 (en) * 2009-03-03 2012-12-11 Givandan S.A. Off-taste masking
WO2011108499A1 (fr) * 2010-03-03 2011-09-09 株式会社エリナ Promoteur de différenciation d'ostéoblastes, composition pharmaceutique pour favoriser l'ossification et aliment de santé contenant un analogue d'auraptène en tant que principe actif
CN102267966B (zh) * 2011-08-01 2013-02-27 华中科技大学 取代的苯并吡喃酮类衍生物及其应用
JP5945861B2 (ja) * 2011-09-29 2016-07-05 学校法人松山大学 医薬組成物及びその製造方法
JP2018110572A (ja) * 2017-01-13 2018-07-19 国立大学法人千葉大学 ＤＧＫδノックアウトマウス及びこれを用いた方法
CN108478568B (zh) * 2018-02-01 2020-08-28 华中农业大学 一种香豆素类化合物在制备单胺氧化酶抑制剂中的用途
CN116650476B (zh) * 2023-05-30 2025-09-09 南华大学附属第一医院 一种化合物、组合物及其在制备治疗心脏病的药物中的应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1770171C3 (de) * 1967-04-14 1979-08-30 Beecham Group Ltd., Brentford, Mddlesex (Grossbritannien) 2,2-Dimethyl-7-alkyl-4-(4-pyridyl)-2H-chromen-5-ole, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneipräparate
GB1497161A (en) * 1975-07-19 1978-01-05 Beecham Group Ltd Naphthyl derivatives
JPH04128224A (ja) * 1989-11-28 1992-04-28 Sankyo Co Ltd クマリン環を有する脳循環代謝改善薬
JP2004131432A (ja) * 2002-10-11 2004-04-30 Kumamoto Technology & Industry Foundation 悪性腫瘍抑制剤
EP1588705A1 (fr) * 2004-04-21 2005-10-26 INTE:LIGAND Software-Entwicklungs und Consulting GmbH Utilisation de dérivés de la coumarine
WO2006024545A1 (fr) * 2004-09-03 2006-03-09 Stichting Voor De Technische Wetenschappen Composes bicycliques naturels condenses et utilisation de ceux-ci comme inhibiteurs de parp et des processus inflammatoires a mediation parp

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006042441A2 *

Also Published As

Publication number Publication date
KR20070068400A (ko) 2007-06-29
EP1802298B1 (fr) 2008-12-31
ATE418980T1 (de) 2009-01-15
WO2006042441A2 (fr) 2006-04-27
DE602005012132D1 (de) 2009-02-12
JP2013063974A (ja) 2013-04-11
JP2008517879A (ja) 2008-05-29
CN101703239A (zh) 2010-05-12
US8044094B2 (en) 2011-10-25
US20070293563A1 (en) 2007-12-20
ES2320686T3 (es) 2009-05-27
CN101043886A (zh) 2007-09-26
WO2006042441A3 (fr) 2006-07-13

Similar Documents

Publication Publication Date Title
US8552055B2 (en) Dietary and pharmaceutical compositions containing tricyclic diterpenes and their derivates and their uses
EP2068863B1 (fr) Ligustilide pour le traitement des maladies du systeme nerveux central
US20100317727A1 (en) Rosemary extracts, dietary and pharmaceutical compostions containing them and their uses
JP2013063974A (ja) 神経伝達障害に関係のある障害を予防および治療するための新規薬剤の製造のための組成物の使用
EP2099318B1 (fr) Utilisations de compositions contenant du carnosol et/ou du rosmanol
US20120149766A1 (en) Dietary and pharmaceutical compositions comprising a sage extract containing a mixture of tricyclic diterpenes and their derivatives and their uses

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070322

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20070928

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 602005012132

Country of ref document: DE

Date of ref document: 20090212

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2320686

Country of ref document: ES

Kind code of ref document: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090430

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090601

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20091001

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091031

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091021

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091021

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090701

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081231

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20130911

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20131016

Year of fee payment: 9

Ref country code: FR

Payment date: 20131009

Year of fee payment: 9

Ref country code: CH

Payment date: 20131014

Year of fee payment: 9

Ref country code: GB

Payment date: 20131016

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20131016

Year of fee payment: 9

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602005012132

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20141021

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150501

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141021

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20150630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141021

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20151126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141022